G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis

Abstract

Covalent modification of histone tails is crucial for transcriptional regulation, mitotic chromosomal condensation, and heterochromatin formation. Histone H3 lysine 9 (H3-K9) methylation catalyzed by the Suv39h family proteins is essential for establishing the architecture of pericentric heterochromatin. We recently identified a mammalian histone methyltransferase (HMTase), G9a, which has strong HMTase activity towards H3-K9 in vitro. To investigate the in vivo functions of G9a, we generated G9a-deficient mice and embryonic stem (ES) cells. We found that H3-K9 methylation was drastically decreased in G9a-deficient embryos, which displayed severe growth retardation and early lethality. G9a-deficient ES cells also exhibited reduced H3-K9 methylation compared to wild-type cells, indicating that G9a is a dominant H3-K9 HMTase in vivo. Importantly, the loss of G9a abolished methylated H3-K9 mostly in euchromatic regions. Finally, G9a exerted a transcriptionally suppressive function that depended on its HMTase activity. Our results indicate that euchromatic H3-K9 methylation regulated by G9a is essential for early embryogenesis and is involved in the transcriptional repression of developmental genes.

Gradual development of a genome‐wide H3‐K9 trimethylation pattern in paternally derived pig pronucleus

“…The species difference in development of the paternal H3-K9 methylation pattern might simply be due to the activity of certain histone methyltransferases (HMTases) in the oocyte cytoplasm. Various H3-K9-specific HMTases have been characterized to date, including SUVAR39 (Rea et al, 2000;Nakayama et al, 2001), G9A (Tachibana et al, 2002), GLP/ Eu-HMTase (Ogawa et al, 2002), SETDB1 (Schultz et al, 2002;Yang et al, 2002;Dodge et al, 2004), and SETDB2 (Mabuchi et al, 2001). Currently, however, it is unknown which activity, or combination of activities, is responsible for development of the paternal H3-m 3 K9 pattern in the pig and whether the activity responsible is absent from, or inhibited in, the mouse fertilized oocyte.…”

Imprinting centers, chromatin structure, and disease

“…Xin et al [2003] studied mouse ES cells and embryos homozygous for an inactivated allele of G9a, which encodes the major H3 Lys9 methyltransferase in euchromatic regions of the nucleus. G9a can methylate in vitro-synthesized H3 in the absence of other histones [Tachibana et al, 2001[Tachibana et al, , 2002. G9a À/À ES cells showed reduced association of dimethyl Lys9 H3 with the Snrpn promoter, and they lost all CpG methylation of the Snrpn promoter.…”

A new perspective on neural tube defects: Folic acid and microRNA misexpression

“…Because so many current mouse models display extreme phenotypes or embryonic lethality, and heterozygotes are usually unaffected, mutations in genes, especially null mutations, do not seem sufficient to explain NTDs (Bell et al, 2003;Bulgakov et al, 2004;Finnell et al, 2002;Friedman and Kaestrer, 2006;Hatakeyama et al, 2004;Hirata et al, 2001;Mathers, 2005;Nagai et al, 2000;Pierani et al, 2001;Sahara et al, 2007;Tachibana et al, 2002;Xu et al, 1999). miRNAs may offer a more subtle deregulation, and there is enough evidence that miRNA genes are under regulation by methylation to add plausibility to the idea (Bak et al, 2008;Han et al, 2007;Lujambio et al, 2007;Weber et al, 2007).…”

“…However, these mouse models often die in utero or shortly after birth and, additionally, few mutant models of caudal closed NTDs exist (Bell et al, 2003;Bulgakov et al, 2004;Finnell et al, 2002;Friedman and Kaester, 2006;Hatakeyama et al, 2004;Hirata et al, 2001;Nagai et al, 2000;Pierani et al, 2001;Sahara et al, 2007;Tachibana et al, 2002;Xu et al, 1999). This is in sharp contrast to what is seen in humans in which spina bifida occulta (a caudal closed NTD) is the most common.…”